Impact of High-Temperature Feeds on Gut Microbiota and MAFLD.

The purpose of this study is to investigate the effects of non-obese MAFLD on the gut microbiota and metabolic pathways caused by high-temperature processed meals. It was decided to divide the eighteen male Sprague-Dawley rats into three groups: the control group, the dry-fried soybeans (DFS) group, and the high-fat diet (HFD) group. Following the passage of twelve weeks, a series of physical, biochemical, histological, and microbiological examinations were carried out. There were distinct pathological abnormalities brought about by each diet. The DFS diet was found to cause the development of fatty liver and to demonstrate strong relationships between components of the gut microbiota, such as Akkermansia and Mucispirillum, and indices of liver health. Diet-induced changes in the gut microbiome have a significant impact on liver pathology in non-obese patients with metabolically altered liver disease (MAFLD), which suggests that dietary interventions that target gut microbiota could be used to manage or prevent the illness.

Elevated triglyceride-glucose index associated with increased risk of diabetes in non-obese young adults: a longitudinal retrospective cohort study from multiple Asian countries.

Objective: Previous studies have confirmed a positive correlation between the Triglyceride-Glucose (TyG) index and future risk of diabetes. However, evidence of this association in non-obese young populations remains limited. This study aims to investigate the relationship between the TyG index and the future risk of diabetes among non-obese young adults. Methods: This retrospective cohort study included 113,509 non-obese young adults from China and 9,549 from Japan. The mean age was 35.73 ± 6.38 years, and 56,469 participants (45.89%) were male. The median follow-up duration was 3.38 years. The association between baseline TyG index and risk of diabetes was examined using Cox proportional hazards regression models. Non-linear relationships between the TyG index and risk of diabetes were identified using cubic splines and smoothed curve fitting in the Cox models. Sensitivity and subgroup analyses were also conducted. Results: After adjusting for covariates, the results indicated a positive correlation between the TyG index and risk of diabetes in non-obese young adults (HR=3.57, 95% CI: 2.92-4.36, P<0.0001). A non-linear relationship was observed with an inflection point at 7.3. The HR to the right of this inflection point was 3.70 (95% CI: 3.02-4.52, P<0.0001), while to the left, it was 0.34 (95% CI: 0.06-1.88, P=0.2161). The robustness of our findings was confirmed through a series of sensitivity analyses and subgroup analyses. Conclusion: This study reveals a positive and non-linear association between the TyG index and risk of diabetes among non-obese young adults. Interventions aimed at reducing the TyG index by lowering triglycerides or fasting glucose levels could substantially decrease the future likelihood of developing diabetes in this population.

Alterations in Choline Metabolism in Non-Obese Individuals with Insulin Resistance and Type 2 Diabetes Mellitus.

The prevalence of non-obese individuals with insulin resistance (IR) and type 2 diabetes (T2D) is increasing worldwide. This study investigates the metabolic signature of phospholipid-associated metabolites in non-obese individuals with IR and T2D, aiming to identify potential biomarkers for these metabolic disorders. The study cohort included non-obese individuals from the Qatar Biobank categorized into three groups: insulin sensitive, insulin resistant, and patients with T2D. Each group comprised 236 participants, totaling 708 individuals. Metabolomic profiling was conducted using high-resolution mass spectrometry, and statistical analyses were performed to identify metabolites associated with the progression from IS to IR and T2D. The study observed significant alterations in specific phospholipid metabolites across the IS, IR, and T2D groups. Choline phosphate, glycerophosphoethanolamine, choline, glycerophosphorylcholine (GPC), and trimethylamine N-oxide showed significant changes correlated with disease progression. A distinct metabolic signature in non-obese individuals with IR and T2D was characterized by shifts in choline metabolism, including decreased levels of choline and trimethylamine N-oxide and increased levels of phosphatidylcholines, phosphatidylethanolamines, and their degradation products. These findings suggest that alterations in choline metabolism may play a critical role in the development of glucose intolerance and insulin resistance. Targeting choline metabolism could offer potential therapeutic strategies for treating T2D. Further research is needed to validate these biomarkers and understand their functional significance in the pathogenesis of IR and T2D in non-obese populations.

CT Quantitation and Prediction of the Risk of Type 2 Diabetes Mellitus in Non-Obese Patients with Pancreatic Fatty Infiltration.

Purpose: To examine the risk of type 2 diabetes mellitus in non-obese patients with pancreatic fatty infiltration through abdominal computed tomography (CT) quantitation. Patients and Methods: We carried out a retrospective analysis of abdominal CT and inpatient medical records of 238 inpatients from July 2019 to April 2021. The patients were divided into a normal non-obese group (BMI < 25, n = 135) and diabetic non-obese group (BMI < 25, n = 103). Abdominal CT-related parameters included body width; mean CT values of the pancreas, liver, and spleen; difference between pancreas and spleen CT values (P-S); pancreas-to-spleen attenuation ratio (P/S); and liver-to-spleen attenuation ratio (L/S). Logistic regression was used to estimate the risk factors for comorbid diabetes in a non-obese population. Results: The P-values of the pancreas CT value, P-S, P/S, body width, and L/S were all <0.05 and correlated to comorbid diabetes in non-obese patients. Worsening pancreatic fatty infiltration increased the risk of developing diabetes. Using a P/S of 1.0 as reference, every successive decrease in this ratio by 0.1 increases patient risk by 3.981, 4.452, 6.037, and 12.937 times. Conclusion: The risk of developing type 2 diabetes mellitus in non-obese patients increases with the degree of pancreatic fatty infiltration as assessed by CT.

Triglyceride glucose index as a predictor for non-alcoholic fatty liver disease: insights from a longitudinal analysis in non-obese individuals.

Background: A substantial portion of non-obese population is afflicted with Non-alcoholic Fatty Liver Disease (NAFLD). The Triglyceride Glucose (TyG) index, a quantifier of insulin resistance magnitude, is determined by the product of fasting plasma glucose and triglyceride concentrations. The relationship between the TyG index and NAFLD within this cohort remains ambiguous. Methods: We conducted a retrospective analysis utilizing datasets acquired from the Dryad digital repository. Non-obese participants (BMI < 25 kg/m2) were enrolled at the Wenzhou Medical Center of Wenzhou People's Hospital between January 2010 and December 2014. Demographic information and biochemical parameters were systematically compiled, and the diagnosis of NAFLD was established through ultrasonographic evidence. Results: This study cohort included 16,172 non-obese participants with a 5-year follow-up, among whom 2,322 (14.36%) developed NAFLD. The disparity between TyG index quartiles in the accumulative incidence of new-onset NAFLD was distinct, with an increasing risk of new-onset NAFLD as the TyG index increased. Participants in highest quartile exhibited the maximum risk of NAFLD. In the fully adjusted model 3, the hazard ratios for NAFLD in Q2, Q3, and Q4 were 2.15 (1.62, 2.87), 2.89 (2.20, 3.80) and 4.58 (3.48, 6.02), respectively. Meanwhile, the TyG index and NAFLD risk showed a highly significant overall correlation (p < 0.0001) and nonlinearity (p < 0.0001) according to the limited cubic splines. In subgroup analysis, a significant interaction was noted between new-onset NAFLD and SBP (<140 mmHg vs. ≥140 mmHg; P for interaction = 0.0114). The SBP < 140 mmHg subgroup demonstrated an enhanced TyG index influence on NAFLD risk (HR = 2.83, 95% CI: 2.48-3.23, p < 0.0001). Conclusion: The TyG index serves as a straightforward instrument for assessing NAFLD risk in non-obese individuals, enabling prompt identification and management in this population segment.

[Triglyceride-glucose index in non-obese individuals: its association with and predictive value for non-alcoholic fatty liver disease].

OBJECTIVE: To investigate the association of triglyceride-glucose index (TyG) with non-alcoholic fatty liver disease (NAFLD) and its diagnostic value for NAFLD in non-obese individuals. METHODS: We retrospectively collected the data of non-obese individuals (BMI < 25 kg/m2) undergoing routine health examination at Second Affiliated Hospital of Xi'an Jiaotong University between May, 2020 and December, 2023, who all received abdominal ultrasound examination for NAFLD screening. The nonlinear relationship between TyG and non-obese NAFLD was explored using restricted cubic splines (RCS), and LASSO regression was used for variable screening; the correlation between TyG and NAFLD risk was analyzed using multivariate logistic regression. The diagnostic value of TyG for non-obese NAFLD was assessed using receiver-operating characteristic (ROC) curves and sensitivity analysis. RESULTS: A total of 3723 non-obese subjects were enrolled in this study, including 432 (11.6%) patients with NAFLD. Compared with the healthy individuals, the patients with NAFLD had significant elevations of systolic and diastolic blood pressures, total cholesterol, triglycerides, LDL-C, blood uric acid, fasting blood glucose, and TyG index and a decreased HDL-C level (P < 0.05). Multivariate logistic regression revealed that for each one-unit increase of TyG, the risk of non-obese NAFLD increased by 2.2 folds (OR=3.22, 95% CI: 2.53-4.12, P < 0.001). Compared with a TyG index in the lowest quartile Q1, a TyG index in the Q2, Q3 and Q4 quartiles was associated with an increased risk of NAFLD by 1.52 folds (OR=2.52, 95% CI: 1.20-5.95), 3.56 folds (OR=4.56, 95% CI: 2.28-10.46), and 8.66-folds (OR=9.66, 95% CI: 4.83-22.18), respectively. The RCS curve demonstrated a significant linear correlation between TyG index and non-obese NALFD risk (P for nonlinear= 0.019). For diagnosing non-obese NALFD, TyG index had an area under ROC curve of 0.819 with a sensitivity of 78.0% and a specificity of 71.2%. CONCLUSION: An increase of TyG index is correlated with increased risks of NAFLD in non-obese individuals and can serve as an indicator for screening early NAFLD in healthy individuals.

A High Fibrosis-4 Index is Associated with a Reduction in the Estimated Glomerular Filtration Rate in Non-obese Japanese Patients with Type 2 Diabetes Mellitus.

Liver fibrosis is associated with non-alcoholic fatty liver disease (NAFLD), and one of the most important risk factors for NAFLD is type 2 diabetes (T2DM). The Fibrosis-4 (FIB-4) index, a noninvasive liver fibrosis score, has been found to be useful for estimating liver fibrosis. Because individuals with non-obese NAFLD were recently reported to be metabolically unhealthy and have a higher risk of T2DM than individuals with obese NAFLD, we hypothesized that the clinical factors related to a high FIB-4 index would differ between non-obese and obese Japanese T2DM patients. Accordingly, we examined the relationship between clinical factors and the FIB-4 index in non-obese and obese Japanese patients with T2DM. We divided 265 patients into two groups by BMI level - a non-obese group (n = 149) and an obese group (n = 116) - and examined the correlation between the FIB-4 index and clinical parameters. Single regression analysis revealed that a high FIB-4 index was correlated with a reduction in the estimated glomerular filtration rate and hypertension in the non-obese group. Importantly, multiple regression analysis showed that only a reduction in the estimated glomerular filtration rate was significantly associated with a high FIB-4 index in the non-obese group. These results demonstrated that non-obese T2DM patients with a high FIB-4 index might be at risk of kidney dysfunction. Our findings may enable the more appropriate treatment of T2DM patients based on BMI level.

Dietary characteristics associated with the risk of non-alcoholic fatty liver disease and metabolic dysfunction-associated steatotic liver disease in non-obese Japanese participants: A cross-sectional study.

Background and Aim: Dietary characteristics associated with non-alcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated steatotic liver disease (MASLD) in non-obese patients remain to be elucidated. This study examined the association of NAFLD and MASLD with dietary characteristics according to obesity status. Methods: We performed a cross-sectional study of 15 135 participants (n = 7568 men and 7567 women) aged 35-74 years using data of annual health checks between 2008 and 2020. Obesity was defined as BMI ≥ 25 kg/m2. Diagnosis of fatty liver was based on abdominal ultrasonography. Fatty-liver-related dietary characteristics were assessed using a self-administered questionnaire. Results: For non-obese participants, NAFLD was found in 31.0% of men and 19.4% of women. Non-obese MASLD was found in 27.6% of men and 18.1% of women. Multivariable-adjusted stepwise logistic regression analysis indicated that, in males, both non-obese NAFLD and non-obese MASLD were significantly and negatively associated with "often eat sesame/nuts", and positively associated with "often eat noodles/rice bowl" and "often eat evening meal" (P < 0.05). For non-obese women, both NAFLD and MASLD were significantly and positively associated with "often eat sweet buns/bread with fillings" (P < 0.05). Adjusted analyses showed that all dietary characteristics were not significantly associated with the risk of NAFLD/MASLD in obese men and women. Conclusion: This cross-sectional study indicates the existence of sex and obesity differences in the association of NAFLD and MASLD with dietary characteristics. Our findings suggest that some dietary characteristics are associated with NAFLD and MASLD prevalence in non-obese Japanese participants.

Update in lean metabolic dysfunction-associated steatotic liver disease.

BACKGROUND: A new nomenclature consensus has emerged for liver diseases that were previously known as non-alcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated fatty liver disease (MAFLD). They are now defined as metabolic dysfunction-associated steatotic liver disease (MASLD), which includes cardiometabolic criteria in adults. This condition, extensively studied in obese or overweight patients, constitutes around 30% of the population, with a steady increase worldwide. Lean patients account for approximately 10%-15% of the MASLD population. However, the pathogenesis is complex and is not well understood. AIM: To systematically review the literature on the diagnosis, pathogenesis, characteristics, and prognosis in lean MASLD patients and provide an interpretation of these new criteria. METHODS: We conducted a comprehensive database search on PubMed and Google Scholar between January 2012 and September 2023, specifically focusing on lean NAFLD, MAFLD, or MASLD patients. We include original articles with patients aged 18 years or older, with a lean body mass index categorized according to the World Health Organization criteria, using a cutoff of 25 kg/m2 for the general population and 23 kg/m2 for the Asian population. RESULTS: We include 85 studies in our analysis. Our findings revealed that, for lean NAFLD patients, the prevalence rate varied widely, ranging from 3.8% to 34.1%. The precise pathogenesis mechanism remained elusive, with associations found in genetic variants, epigenetic modifications, and adaptative metabolic response. Common risk factors included metabolic syndrome, hypertension, and type 2 diabetes mellitus, but their prevalence varied based on the comparison group involving lean patients. Regarding non-invasive tools, Fibrosis-4 index outperformed the NAFLD fibrosis score in lean patients. Lifestyle modifications aided in reducing hepatic steatosis and improving cardiometabolic profiles, with some medications showing efficacy to a lesser extent. However, lean NAFLD patients exhibited a worse prognosis compared to the obese or overweight counterpart. CONCLUSION: MASLD is a complex disease comprising epigenetic, genetic, and metabolic factors in its pathogenesis. Results vary across populations, gender, and age. Limited data exists on clinical practice guidelines for lean patients. Future studies employing this new nomenclature can contribute to standardizing and generalizing results among lean patients with steatotic liver disease.

Accelerated onset of diabetes in non-obese diabetic mice fed a refined high-fat diet.

AIM: Type 1 diabetes results from autoimmune events influenced by environmental variables, including changes in diet. This study investigated how feeding refined versus unrefined (aka 'chow') diets affects the onset and progression of hyperglycaemia in non-obese diabetic (NOD) mice. METHODS: Female NOD mice were fed either unrefined diets or matched refined low- and high-fat diets. The onset of hyperglycaemia, glucose tolerance, food intake, energy expenditure, circulating insulin, liver gene expression and microbiome changes were measured for each dietary group. RESULTS: NOD mice consuming unrefined (chow) diets developed hyperglycaemia at similar frequencies. By contrast, mice consuming the defined high-fat diet had an accelerated onset of hyperglycaemia compared to the matched low-fat diet. There was no change in food intake, energy expenditure, or physical activity within each respective dietary group. Microbiome changes were driven by diet type, with chow diets clustering similarly, while refined low- and high-fat bacterial diversity also grouped closely. In the defined dietary cohort, liver gene expression changes in high-fat-fed mice were consistent with a greater frequency of hyperglycaemia and impaired glucose tolerance. CONCLUSION: Glucose intolerance is associated with an enhanced frequency of hyperglycaemia in female NOD mice fed a defined high-fat diet. Using an appropriate matched control diet is an essential experimental variable when studying changes in microbiome composition and diet as a modifier of disease risk.

Predictors of High Cardiovascular Risk Among Nonobese Patients with Type 2 Diabetes and Non-Alcoholic Fatty Liver Disease in a Chinese Population.

Purpose: This study aims to investigate cardiovascular risk factors in nonobese patients with type 2 diabetes (T2DM) and non-alcoholic fatty liver disease (NAFLD) and to determine whether they might be used to predict high-risk individuals effectively. Patients and Methods: This cross-sectional study included 245 nonobese patients with T2DM who underwent FibroTouch in the National Metabolic Management Center of the Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University from January 2021 to December 2022. All individuals were divided into NAFLD and non-NAFLD groups. Patients with NAFLD were further grouped by UAP tertiles (T1, T2 and T3). We created a Cardiovascular Score (total scale: 0-5 points; ≥3 points was defined as high-risk individual) based on baPWV, carotid ultrasound, and urinary microalbumin creatinine ratio (UA/CR) to assess the risk of cardiovascular disease in non-obese T2DM patients with NAFLD. Risk factors were evaluated using univariate and multivariate analysis. The performance of risk factors was compared according to the area under the receiver operating characteristic (ROC) curve. Results: Atherogenic index of plasma (AIP), atherosclerosis index (AI), prevalence of hypertension, body mass index (BMI) and homeostatic model assessment of insulin resistance (HOMA-IR) were higher in the NAFLD group compared to the non-NAFLD group. In T3 group, AIP, AI, BMI and HOMA-IR were higher than those of T1 group. Multivariate logistic regression showed that age, systolic blood pressure, low-density lipoprotein-cholesterol (LDL-C) and AIP were risk factors for cardiovascular disease among nonobese patients with T2DM and NAFLD. The area under the ROC curve for age, systolic blood pressure, LDL-C and AIP were 0.705, 0.688, 0.738 and 0.642, respectively. The area under the ROC curve was 0.895 when combining them. Conclusion: Age, systolic blood pressure, AIP and LDL-C are all independent risk factors for cardiovascular disease in non-obese individuals with T2DM and NAFLD, which can be combined to identify high-risk populations and carry out intervention.

Impact of nonalcoholic fatty liver disease on the risk of gallbladder polyps in lean and non-obese individuals: A cohort study.

BACKGROUND: The association between non-obese or lean nonalcoholic fatty liver disease (NAFLD) and gallbladder polyps (GBPs) has not yet been evaluated. We aimed to determine whether NAFLD is an independent risk factor for the development of GBPs, even in non-obese and lean individuals. METHODS: We analyzed a cohort of 331 208 asymptomatic adults who underwent abdominal ultrasonography (US). The risk of GBP development was evaluated according to the obesity and NAFLD status. RESULTS: The overall prevalence of NAFLD and GBPs ≥ 5 mm was 28.5% and 2.9%, respectively. The prevalence of NAFLD among 160 276 lean, 77 676 overweight and 93 256 obese participants was 8.2%, 31.2%, and 61.1%, respectively. Individuals with NAFLD had a significantly higher incidence of GBPs with a size of ≥ 5 mm [adjusted odds ratio (OR) = 1.18; 95% confidence interval (CI): 1.11-1.25]. A higher body mass index and its categories were also significantly associated with an increased risk of GBPs ≥ 5 mm. Moreover, risk of GBPs ≥ 5 mm was significantly increased even in NAFLD individuals who are not obese (lean: adjusted OR = 1.36, 95% CI: 1.19-1.54; overweight: adjusted OR = 1.14, 95% CI: 1.03-1.26, respectively). CONCLUSIONS: Non-obese/lean NAFLD is an independent risk factor for GBP development, suggesting that NAFLD may play an important role in the pathogenesis of GBPs regardless of the obesity status. Therefore, a more thorough evaluation for GBPs may be necessary when hepatic steatosis is detected on abdominal US, even in non-obese or lean individuals.

Prevalence and Risk Factors of Non-Alcoholic Fatty Liver Disease (NAFLD) in Non-Obese Patients with Schizophrenia: A Retrospective Study.

Background: To assess the prevalence and risk factors of NAFLD in non-obese patients with schizophrenia in a public psychiatric hospital in China. Methods: A total of 1,305 adult inpatients with schizophrenia in 2019 were included in this retrospective study. Body mass index (BMI) ≥ 25 kg/m2 was considered obese, and BMI < 25 kg/m2 was considered non-obese. We obtained the data from electronic records of the Affiliated Brain Hospital of Guangzhou Medical University. Results: A total of 1,045 non-obese patients and 260 obese patients were included in this study. The prevalence of NAFLD in non-obese patients was 25.0%, and it was much lower that in the obese patients (25.0% vs 64.6%, p < 0.001). Among the non-obese patients, there were significant differences in age, BMI, alanine aminotransferase (ALT), metabolic indices, and the prevalence of diabetes and hypertension between patients with NAFLD and patients without NAFLD. According to the results of binary logistic regression analysis, age, BMI, ALT, triglyceride (TG) and diabetes were significantly related to NAFLD among non-obese patients with schizophrenia. In contrast, HDL-C was was negatively associated with NAFLD among non-obese patients. Conclusion: This study suggested that NAFLD was common in patients with schizophrenia, even in non-obese patients with schizophrenia. In non-obese patients with schizophrenia, age, BMI, ALT, TG and diabetes are significantly associated with NAFLD. Moreover, HDL-C level was an independent protective factor against NAFLD. Given the adverse outcomes of NAFLD, it is necessary to increase awareness of NAFLD in patients with schizophrenia, especially in non-obese patients with schizophrenia.

A New Non-Obese Steatohepatitis Mouse Model with Cardiac Dysfunction Induced by Addition of Ethanol to a High-Fat/High-Cholesterol Diet.

Non-obese metabolic dysfunction-associated steatotic liver disease (MASLD) has been associated with cardiovascular-related mortality, leading to a higher mortality rate compared to the general population. However, few reports have examined cardiovascular events in non-obese MASLD mouse models. In this study we created a mouse model to mimic this condition. In this study involving seven-week-old C57BL/6J male mice, two dietary conditions were tested: a standard high-fat/high-cholesterol diet (STHD-01) and a combined diet of STHD-01 and ethanol. Over periods of 6 and 12 weeks, we analyzed the effects on liver and cardiac tissues using various staining techniques and PCR. Echocardiography and blood tests were also performed to assess cardiac function and liver damage. The results showed that mice on the ethanol-supplemented STHD-01 diet developed signs of steatohepatitis and cardiac dysfunction, along with increased sympathetic activity, as early as 6 weeks. At 12 weeks, more pronounced exacerbations accompanied with cardiac dilation, advanced liver fibrosis, and activated myocardial fibrosis with sympathetic activation were observed. This mouse model effectively replicated non-obese MASLD and cardiac dysfunction over a 12-week period using a combined diet of STHD-01 and ethanol. This dietary approach highlighted that both liver inflammation and fibrosis, as well as cardiac dysfunction, could be significantly worsened due to the activation of the sympathetic nervous system. Our results indicate that alcohol, even when completely metabolized on the day of drinking, exacerbates the progression of non-obese MASLD and cardiac dysfunction.

The metabolic profiles and body composition of non-obese metabolic associated fatty liver disease.

Background/purpose: Metabolic-associated fatty liver disease (MAFLD) is a major cause of chronic liver disease worldwide and is generally thought to be closely related to obesity and diabetes. However, it also affects non-obese individuals, particularly in Asian cultures. Methods: Healthy physical examination subjects and MAFLD patients were included in the endocrinology department of Jiangsu Provincial Hospital of Traditional Chinese Medicine. MAFLD was defined as fatty liver in imaging without virus infection, drug, alcohol, or other known causes of chronic liver disease. Non-obese MAFLD was defined as MAFLD in non-obese subjects (BMI<25 kg/m2). Results: The final analysis comprised 1047 participants in total. Of 946 MAFLD patients, 162 (17.12%) were diagnosed with non-obese MAFLD. Non-obese MAFLD patients were older, had lower alanine aminotransferase (ALT), triglyceride, and waist circumference, but had higher high density lipoprotein cholesterol (HDL-c) than obese MAFLD patients. Compared with non-obese healthy controls, non-obese MAFLD patients had higher BMI, ALT, gamma-glutamyl transferase (GGT), uric acid (UA), triglycerides (TG), and low density lipoprotein cholesterol (LDL-c). In terms of body composition, body fat mass (BFM), waist-hip ratio (WHR), percent body fat (PBF), visceral fat area (VFA), and fat mass index (FMI) were lower in non-obese healthy controls than non-obese MAFLD patients. A binary logistic regression analysis revealed that non-obese MAFLD was linked with lower GGT and higher HDL-c. Conclusion: In this study cohort, non-obese MAFLD was present at a prevalence of 13.90%. In contrast to non-obese healthy controls, non-obese MAFLD patients exhibited different metabolic profiles, but they also had different body compositions.

Association between the ZJU index and risk of new-onset non-alcoholic fatty liver disease in non-obese participants: a Chinese longitudinal prospective cohort study.

Background: Non-alcoholic fatty liver disease (NAFLD) is increasingly observed in non-obese individuals. The ZJU (Zhejiang University) index has been established as a new and efficient tool for detecting NAFLD, but the relationship between the ZJU index and NAFLD within non-obese individuals still remains unclear. Methods: A post-hoc evaluation was undertaken using data from a health assessment database by the Wenzhou Medical Center. The participants were divided into four groups based on the quartile of the ZJU Index. Cox proportional hazards regression, Kaplan-Meier analysis and tests for linear trends were used to evaluate the relationship between the ZJU index and NAFLD incidence. Subgroup analysis was conducted to test the consistency of the correlation between ZJU and NAFLD in subsgroups. Receiver operative characteristic (ROC) curve analysis was performed to evaluate the predictive performance of the ZJU index, compared with the Atherogenic index of plasma (AIP) and Remnant lipoprotein cholesterol (RLP-C) index. Results: A total of 12,127 were included in this study, and 2,147 participants (17.7%) developed NAFLD in 5 years follow-up. Participants in higher ZJU quartiles tended to be female and have higher liver enzymes (including ALP, GGT, ALT, AST), GLU, TC, TG, LDL and higher NAFLD risk. Hazard Ratios (HR) and 95% confidence intervals (CI) for new-onset NAFLD in Q2, Q3, and Q4 were 3.67(2.43 to 5.55), 9.82(6.67 to 14.45), and 21.67(14.82 to 31.69) respectively in the fully adjusted model 3. With increased ZJU index, the cumulative new-onset NAFLD gradually increased. Significant linear associations were observed between the ZJU index and new-onset NAFLD (p for trend all<0.001). In the subgroup analysis, we noted a significant interaction in sex, with HRs of 3.27 (2.81, 3.80) in female and 2.41 (2.21, 2.63) in male (P for interaction<0.01). The ZJU index outperformed other indices with an area under the curve (AUC) of 0.823, followed by AIP (AUC=0.747) and RLP-C (AUC=0.668). Conclusion: The ZJU index emerges as a promising tool for predicting NAFLD risk in non-obese individuals, outperforming other existing parameters including AIP and RLP-C. This could potentially aid in early detection and intervention in this specific demographic.

New aspects characterizing non-obese NAFLD by the analysis of the intestinal flora and metabolites using a mouse model.

Non-alcoholic fatty liver disease (NAFLD) is a major public health problem due to the high incidence affecting approximately one-third of the world's population. NAFLD is usually linked to obesity and excessive weight. A subset of patients with NAFLD expresses normal or low body mass index; thus, the condition is called non-obese NAFLD or lean NAFLD. However, patients and healthcare professionals have little awareness and understanding of NAFLD in non-obese individuals. Furthermore, preclinical results from non-obese animal models with NAFLD are unclear. Gut microbiota and their metabolites in non-obese/lean-NAFLD patients differ from those in obese NAFLD patients. Therefore, we analyzed the biochemical indices, intestinal flora, and intestinal metabolites in a non-obese NAFLD mouse model established using a methionine-choline-deficient (MCD) diet. The significantly lean MCD mice had a remarkable fatty liver with lower serum triglyceride and free fatty acid levels, as well as higher alanine transaminase and aspartate transaminase levels than normal mice. 16S RNA sequencing of fecal DNA showed that the overall richness and diversity of the intestinal flora decreased in MCD mice, whereas the Firmicutes:Bacteroidota ratio was increased. g_Tuzzerella, s_Bifidobacterium pseudolongum, and s_Faecalibaculum rodentium were the predominant species in non-obese NAFLD mice. Fecal metabolomics using liquid chromatography-tandem mass spectrometry revealed the potential biomarkers for the prognosis and diagnosis of non-obese NAFLD, including high levels of tyramine glucuronide, 9,12,13-TriHOME, and pantetheine 4'-phosphate, and low levels of 3-carbamoyl-2-phenylpropionaldehyde, N-succinyl-L,L-2,6-diaminopimelate, 4-methyl-5-thiazoleethanol, homogentisic acid, and estriol. Our findings could be useful to identify and develop drugs to treat non-obese NAFLD and lean NAFLD. IMPORTANCE: Patients and healthcare professionals have little awareness and understanding of NAFLD in non-obese individuals. In fact, about 40% of people with NAFLD worldwide are non-obese, and nearly one-fifth are lean. Lean NAFLD unfortunately may be unnoticed for years and remains undetected until hepatic damage is advanced and the prognosis is compromised. This study focused on the lean NAFLD, screened therapeutic agents, and biomarkers for the prognosis and diagnosis using MCD-induced male C57BL/6J mice. The metabolites tyramine glucuronide, 9,12,13-TriHOME, and pantetheine 4'-phosphate, together with the predominant flora including g_Tuzzerella, s_Bifidobacterium pseudolongum, and s_Faecalibaculum rodentium, were specific in non-obese NAFLD mice and might be used as targets for non-obese NAFLD drug exploration. This study is particularly significant for non-obese NAFLDs that need to be more actively noticed and vigilant.

Triglycerides Mediate the Influence of Body Mass Index on Non-Alcoholic Fatty Liver Disease in a Non-Obese Chinese Population with Normal Low-Density Lipoprotein Cholesterol Levels.

INTRODUCTION: Over 25% of the world's population has non-obese or lean non-alcoholic fatty liver disease (NAFLD), and the prevalence is higher than average in Asia. The present study focused on the relationship between body mass index (BMI) and non-obese NAFLD in non-overweight people in China, particularly the influence of triglycerides (TG) in the pathogenesis of non-obese NAFLD. The findings suggest new treatments for NAFLD patients with normal BMI, as well as provide an early warning system for the understanding and prevention of NAFLD in non-obese patients. METHODS: This cross-sectional study enrolled 159,959 Chinese subjects with BMI <24 kg/m2 and normal levels of low-density lipoprotein cholesterol (LDL-c). The average age was 40.21 ± 13.88 years, and males accounted for 45.7%. A total of 15,907 (9.94%) patients with NAFLD were diagnosed by ultrasonography. Biochemical indicators were measured using an automated analyzer (Abbott AxSYM). The BMI (kg/m2) was calculated from the weight (kg)/height in square meters (m2). The BMI quartile was used as the column-stratified variable to determine the baseline distribution, and logistic regression analysis was used to assess the relationship between NAFLD and its risk factors, with multiple logistic regression used to assess the relationships between BMI or TG and NAFLD and multivariate linear regression used to analyze the association between BMI and TG, while mediation analysis was used to assess the mediation effect of TG. RESULTS: After adjustment of all covariates, the odds ratios were 1.788 (95% CI: 1.749-1.829; p < 0.00001) and 1.491 (95% CI: 1.451-1.532; p < 0.00001) for the association between BMI and TG with NAFLD incidence. The multivariate linear regression coefficient of BMI and TG was ß = 0.027 (95% CI: 0.023-0.030; p < 0.00001). Mediation analysis showed that BMI contributed to 10.81% of lean NAFLD with a mediation effect of 2.98%. CONCLUSION: In a Chinese population with BMI <24 kg/m2 and normal LDL-c levels, BMI and TG were found to be independent predictors of NAFLD. The direct effect of BMI on non-obese NAFLD was 10.41%. The TG level was found to partially mediate the association.

Effect of probiotics supplementation on liver stiffness and steatosis in patients with NAFLD.

Background and Aim: To compare the effects of probiotics on liver stiffness and steatosis in obese and non-obese patients with nonalcoholic fatty liver disease (NAFLD),the pragmatic clinical trial included 50 obese body mass index (BMI) ≥25 kg/m2 and 50 non-obese NAFLD BMI <25 kg/m2 age and sex-matched patients. Materials and Methods: Fibroscan with controlled attenuated parameter (CAP) was done at day 0 and at the end of 6 months. Probiotics supplementation was provided for both groups for 6 months along with lifestyle modifications. Results: At inclusion, both groups had comparable characteristics except BMI, metabolic syndrome and waist circumference (WC). Beneficial changes occurred in BMI (p=0.024), WC (p=0.045), ALT (p=0.024), total cholesterol (p=0.016), LDL (p=0.025) and triglyceride (p=0.021) of obese group, systolic blood pressure (p=0.003) and LDL level (p=0.018) in non-obese group. No significant change was observed in liver enzymes and glycemic profiles. Significant improvement in CAP was observed in both groups. But after adjusting for changes in BMI and WC, the change in CAP among non-obese participants were significantly higher compared to obese, mean change of 19.33±48.87 and 16.02±51.58 dB/m in non-obese and obese patients, respectively; p=0.044). Conclusion: Probiotics improve CAP/ steatosis in both obese and non-obese NAFLD patients and improvement was higher in non-obese, irrespective of BMI change.

Association of adipocyte size and SREBP-1c in visceral and subcutaneous adipose tissue in non-obese type 2 diabetes mellitus.

OBJECTIVE: Non-obese type 2 diabetes seems to be common in India; hence the current study tried to understand the pathogenesis of diabetes in this group focusing on the role of adipocytes especially abdominal fat compartment. Comparison was made between non-obese subjects with newly detected diabetes and those without diabetes, in relation to levels of adipogenic factor and adipokines in pre-adipocytes and mature adipocytes respectively. RESEARCH DESIGN METHODS: Non-obese subjects (BMI-18-25 Kg/m2) were consecutively selected of whom 15 had newly-detected, treatment naïve type 2 diabetes (HbA1% ≥6.5) while 25 were control (HbA1c% ≤5.6). We examined the expression of adipocyte differentiation factor - SREBP-1c from preadipocytes and adipocyte specific adipokines- HMW isoform and total adiponectin, leptin, FABP-4, TNF-α and IL-6 from adipocytesisolated from abdominal visceral and subcutaneous adipose tissues (VAT and SCAT) by RT-PCR and as well as from serum by ELISA. Size of cultured adipocytes was measured in a fully automated imaging system microscope. RESULT: Both in SCAT and VAT, SREBP-1c and adiponectin had significantly lower expression along with increased mRNA level of inflammatory adipokinesdiabetes.Average adipocyte size and frequency of large(hypertrophied) adipocytes were comparatively higher in T2DM subjects and had significant negative correlation with SREBP-1c. HMW adiponectin level significantly reduced in the secretion from VAT and SCAT of T2DM subjects compared to control. CONCLUSION: Reduced expression of SREBP-1c in preadipocytes may lead to increased number of hypertrophied adipocytes in T2DM. Therefore, these dysfunctional hypertrophied adipocytes could cause imbalanced expression of insulin resistant and insulin sensitive adipokines.